AUP1 p.Leu43Leu

Variant names:

• chr2-74529420-A-A
• NM_181575.5:c.

Your query was ambiguous. Multiple possible variants found:

• chr2-74529421--
• chr2-74529421-G-A
• chr2-74529421-G-T
• chr2-74529421-G-C
• chr2-74529421-GAG-TAA
• chr2-74529421-GAG-CAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181575.5(AUP1):​c. variant causes a exon region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AUP1 NM_181575.5 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510
• Publications: 0 publications found

Genes affected

AUP1 (HGNC:891): (AUP1 lipid droplet regulating VLDL assembly factor) The protein encoded this gene is involved in several pathways including quality control of misfolded proteins in the endoplasmic reticulum and lipid droplet accumulation. Lipid droplets are organelles in the cytoplasm that store neutral lipids such as cholesterol esters and trigylycerides to prevent the overabundance of free cholesterol and fatty acids in cells, but also to act as storage for other metabolic processes, such as membrane biogenesis. Reduced expression of this gene results in reduced lipid droplet clustering, a function that is dependent on ubiquitination of the protein. This protein contains multiple domains including a hydrophobic N-terminal domain, an acetyltranferase domain, a ubiquitin-binding CUE domain, and a UBE2B2-binding domain (G2BR). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

HTRA2 (HGNC:14348): (HtrA serine peptidase 2) This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

HTRA2 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181575.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUP1	NM_181575.5	MANE Select	c.		exon_region	Exon 2 of 12	NP_853553.1	Q9Y679-2
	AUP1	NR_126510.2		n.		exon_region	Exon 2 of 12
	AUP1	NR_126511.2		n.		exon_region	Exon 2 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AUP1	ENST00000377526.4	TSL:1 MANE Select	c.		exon_region	Exon 2 of 12	ENSP00000366748.3	Q9Y679-2
	AUP1	ENST00000425118.5	TSL:1	n.		exon_region	Exon 2 of 12	ENSP00000403430.1	Q9Y679-3
	AUP1	ENST00000463900.5	TSL:1	n.		exon_region	Exon 2 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.051

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-74756547;